Enantioselective and Z/E-selective conjugate addition of α-substituted cyanoacetates to acetylenic esters catalyzed by bifunctional ruthenium and iridium complexes

Article abstract of DOI:10.1002/anie.201003585

Metal-based catalysts: The title reaction provided the chiral adducts in high yields, excellent enantiomeric excess, and high Z/E selectivity. A combined NMR/DFT study revealed a key intermediate for the stereoselective reaction and a possible reaction me

Full text of DOI:10.1002/anie.201003585

Angewandte
Chemie
DOI: 10.1002/anie.201003585
Synthetic Methods
Enantioselective and Z/E-Selective Conjugate Addition of
a-Substituted Cyanoacetates to Acetylenic Esters Catalyzed by
Bifunctional Ruthenium and Iridium Complexes**
Yasuharu Hasegawa, Ilya D. Gridnev, and Takao Ikariya*
Catalytic and stereoselective formation of quaternary carbon
centers remains a significant challenge in organic synthetic
chemistry.[1] Metal-based catalytic methods including asym-
metric alkylation and arylation of carbonyl compounds as
well as enantioselective Diels–Alder reactions have been
successfully applied for the creation of compounds with chiral
quaternary carbon centers.[2] Asymmetric conjugate addition
of pronucleophiles to a,b-unsaturated carbonyl groups pres-
ents one of the most powerful and atom-economic synthetic
approaches to access enantiomerically enriched quaternary
carbon skeletons for the synthesis of biologically active
compounds. However, the chiral metal-based catalyst systems
for enantioselective conjugate addition remain relatively rare,
being limited to multimetal chiral catalysts[1f,g,3] and chiral
metal–enolates.[4] Our research group has developed a highly
efficient asymmetric conjugate addition of 1,3-dicarbonyl
groups to cyclic enones and nitroalkenes with our bifunctional
chiral amido Ru catalysts 1[5] [Ru(Tsdpen)(h6-arene)]
between a-substituted cyanoacetates and acetylenic esters
using bifunctional Ru (1) and Ir (2) catalysts to yield chiral
adducts having a quaternary carbon center. Moreover, NMR
and computational studies revealing the origin of enantiose-
lectivity in this reaction are also reported.
We have found that the conjugate addition of cyanoace-
tate 3 to acetylenic diester 4a in the presence of bifunctional
Ru (1) or Ir (2) catalysts (cyanoacetate/acetylenic ester/cat. =
100:100:1) at 08C gave the corresponding chiral adducts 5
with good to excellent enantiomeric excess and Z/E selectiv-
ity in almost quantitative yields (Scheme 1). Table 1 lists
representative results for the reaction (see the Supporting
Information for more details). Chiral Ru and Ir complexes
work equally well for this reaction, in contrast to the reaction
of cyanoacetate 3a and diazoesters,[8] in which the chiral Ir
catalyst was far superior to the Ru catalyst.
(Tsdpen:
N-(p-toluenesulfonyl)-1,2-diphenylethylenedia-
mine).[6] The use of a-cyanoacetate as a pronucleophile
combined with diazoesters in the presence of bifunctional
chiral Ir amido catalysts 2[7] [Cp*Ir(Tsdpen)] (Cp* = h5-C5-
(CH3)5) also resulted in the direct amination of activated
cyanoacetate to provide products with enantiomerically
enriched tertiary carbon centers.[8] Preliminary mechanistic
studies showed that the key stage of the catalytic cycle is the
deprotonation of the acidic pronucleophile with the chiral
amido catalyst which leads to the stereoselective formation of
an N-bound amine complex.[6c] The resulting amine complex
bearing a metal-bound nucleophile readily reacts with
À
suitable electrophiles to give C N bond-formation products
in a highly stereoselective manner.[8] We reasoned that other
electrophiles may also react with this catalyst–substrate
complex in a similar way to afford new enantioselective
catalytic transformations. Herein, we report an enantioselec-
À
tive and Z/E-selective catalytic C C bond-forming reaction
Scheme 1. Enantioselective reaction of a-cyanoesters and acetylenic
esters. Reaction carried out with a 1:1 ratio of substrates. S/C:
substrate to catalyst ratio.
[*] Y. Hasegawa, Prof. Dr. I. D. Gridnev, Prof. Dr. T. Ikariya
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2637
E-mail: tikariya@apc.titech.ac.jp
As seen in Table 1, the stereochemical outcome of the
reaction is significantly influenced by the structures of the
catalysts as well as the reaction conditions. The optimal
catalysts are 1b and 2b with the Tsdpen ligand (entries 1 and
2; aryl = hexamethylbenzene for the Ru catalyst and aryl =
Cp* for the Ir catalyst). Other Ru complexes with mesitylene
(1d) and p-cymene (1e) aryl groups gave unsatisfactory
[**] This work was financially supported by a Grant-in-Aid from the
Ministry of Education, Culture, Sports, Science and Technology
(Japan, No. 18065007, 22225004) and by The G-COE Program.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003585.
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Table 1: Results of the enantioselective addition of cyanoacetates 3 to acetylenic esters 4 promoted by
by 6a or 6b, respectively
(Scheme 3). In these adducts, the
orientation of the acceptor toward
the amine complex bearing cyanoa-
cetate anion, 6a or 6b, has a critical
importance for determining the
enantioselectivity. Noticeably, the
enantioface of the N-bound cyano-
acetate anion used for the coordi-
nation of substrate is opposite for
both adducts: Si face for 7a and
chiral catalysts 1 or 2.[a]
Entry Cyanoacetate Acetylenic ester Cat. Solvent
Yield [%][b] Z/E
ee [%] (Z/E)[c]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3a
3a
3a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
1a
1b
1c
1d
1e
1b
1b
2a
2b
2c
1b
1b
1b
1b
1b
1b
toluene
toluene
toluene
toluene
toluene
CH2Cl2
97
97
98
97
97
98
20/1
20/1
23/1
14/1
6/1
86/22
91/52
83/25
79/13
43/04
82/81
72/72
84/10
90/23
81/10
89/n.d.
92/27
95/05
2/1
2/1
Et(Me)2COH 99
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH3CN
96
96
95
98
99
99
99
99
99
20/1
20/1
23/1
20/1
17/1
20/1
1/22 n.d./79
1/2
1/2
9
À
Re face for 7b. Hence, the C C
10
11
12
13
14
15
16
bond formation would yield inter-
mediates 8a and 8b—with opposite
configuration at the benzylic carbon
atoms—which are precursors of the
products (S)-5a and (R)-5a, respec-
tively.
65/79
0/0
[a] Unless otherwise noted, the reactions were carried out by the slow addition of 4 with a syringe pump
to a solution of 3 and the chiral amido catalyst in 5 mL of solvent for 20 minutes and subsequent stirring
for 24 hours. The molar ratio of cyanoacetate/acetylenic ester/catalyst=100:100:1. [b] Yield of isolated
product after column chromatography on silica gel. [c] Determined by HPLC on a chiral stationary phase
using a Chiralpak AD-H column (4.6 mmꢀ250 mm). n.d.=not determined.
For the computational study, we
have used the Ru–Tsdpen complex
1b because it provides slightly
better enantioselectivities than 2a.
We have optimized the structures of
results in terms of enantioselectivity and the Z/E selectivity
(entries 3–5). Choice of the solvent has a significant influence
on the configuration of the products. Nonpolar solvents like
toluene or dichloromethane gave high enantioselectivity,
while polar solvents lead to a dramatic decrease of the
ee values and the Z/E selectivities (entries 2, 6, and 7). The a-
phenyl-a-cyanoacetates (3b–d), which have substituted aro-
matic rings, reacted with 4a in toluene catalyzed by the chiral
Ru catalyst (1b) at 08C for 24 hours and gave the chiral
adduct with 89–95% ee in excellent yields regardless of the
electronic effect of the substituents (entries 11–13). The
reaction of cyanoacetate 3a and the acetylenic monoester
4b with the chiral Ru catalyst 1b gave the corresponding
adduct with excellent E selectivity albeit with modest ee val-
ues (entries 14–16). Thus, our approach provides sufficiently
high ee values with much higher Z/E ratios than those of the
reported reaction promoted by organocatalysts.[9]
1
Scheme 2. NOE interactions observed in the phase-sensitive 2D H–1H
NOESY spectrum (400 MHz, CD2Cl2, 223 K) of the sample prepared by
the addition of 1.5 equivalents of cyanoacetate 3a to the amido Ru
complex 1b. See the Supporting Information for more details. Ts=4-
toluenesulfonyl.
the adducts 7a and 7b and found two viable transition states
(TSS and TSR, respectively) for the C C bond-formation
À
To gain further insight into the reaction mechanisms, we
elucidated the structure of the intermediate, N-bound Ru
catalyst–substrate complexes 6a and 6b in solution
(Scheme 2). The reaction of complex 1b[10] with a-cyanoace-
tate 3a yielded the equilibrium mixture of 6a and 6b in a
reversible and stereoselective manner—as was observed
previously with chiral Ir complexes.[8] From the 13C DEPT
and HMBC spectra measured at À558C, we have located the
positions of nonprotonated carbon atoms of 6a,b in the
13C NMR spectrum. The deprotonated anionic carbon atoms
resonate at d = 58.7 ppm and d = 56.5 ppm in 6a and 6b,
respectively. Whereas the nitrile carbon atom is notably
shifted downfield compared to free substrate 3a (d =
136.7 ppm in 6a versus d = 117.3 ppm in 3a). These data
confirm N-binding of the substrate in 6a,b.[8]
step that would each proceed to the intermediates 8a,b
(Scheme 3, Figure 1). Formation of either 7a or 7b is
exothermic; they have similar structures appropriate for the
concerted activation. However, 7b is 9.4 kcalmolÀ1 less stable
than 7a. This difference in the stability originates from the
steric interactions of the loose carbomethoxy group with the
substituents on the anionic carbon atom. Similarly, owing to
the smaller steric interactions of the tert-butoxycarbonyl
À
substituent, the transition state of the C C bond-formation
step resulting in the S product is 9.7 kcalmolÀ1 lower in energy
compared to the unfavorable transition state that leads to the
R product. Thus, we have found a structural reason for the
strong bias towards the enantioselective formation of the
S product that is in accord with the experimentally deter-
mined sense of enantioselection. The experimental ee values
are, however, lower than might be expected in view of such a
substantial energy difference. This outcome might be
In computational work we have located adducts 7a and 7b
in which the substrate 4a is activated in a concerted manner
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would yield a hydroxyallene intermediate 9a with equal
potential for transferring the proton to two alternative
positions (Scheme 4). We have located a transition state for
the direct proton transfer from the bent allenic intermediate
10a to the catalyst product, namely complex 11a (Scheme 4).
The detailed computational study of the internal rotation in
the allenic fragment transforming 8a to 10a, which have bent
structures owing to 1,1-oxo substitution,[11,12] will be reported
in a full paper.
À
Scheme 3. Alternative pathways for C C bond formation leading to
different enantiomers of the reaction product. R=C(CH3)3.
Scheme 4. Z-selective proton transfer from the amine nitrogen atom
to the allenic carbon atom. R=C(CH3)3.
In summary, the bifunctional chiral amido Ru and Ir
complexes have efficiently promoted the catalytic asymmetric
conjugate addition of a-substituted cyanoacetates to acety-
lenic esters to provide the corresponding chiral adducts in
high yields and with excellent ee values and Z/E selectivity.
The deprotonation of cyanoacetates using the chiral amido
complex would lead to the formation of the N-bound nitrile
complexes bearing a cyanoacetate anion. The enantioselec-
À
tive C C bond formation occurs through the sterically
favorable coordination of the acetylenic ester to the N-
bound complex 6a. The subsequent proton transfer occurs
intramolecularly, resulting in the high Z/E selectivity of the
reaction.
Experimental Section
General experimental procedure for the conjugate addition: Under
an argon atmosphere at 08C, 4a (62 mL, 0.50 mmol) was added slowly
(over 20 min using a syringe pump) to a solution of 3a (108 mg,
0.50 mmol) in toluene (5 mL) containing the amido catalyst 1a
(3.1 mg, 5 mmol). The reaction mixture was then stirred for 24 h at
08C. The molar ratio of cyanoacetate/acetylenic ester/catalyst =
100:100:1. After evaporation of the solvent with a vacuum pump,
the crude product was purified with by column chromatography on
silica gel (eluent: n-hexane/ethyl acetate 99:1) to give the desired
adduct 5a with a Z/E ratio of 20:1 in 97% yield (348 mg). The
ee value of the major isomer was 91% ee. All products were analyzed
Figure 1. Optimized structures of the transition states TSR and TSR.
Computational studies were performed at the B3LYP/SDD level of
theory with an additional diffuse function for sulfur. The v° values are
imaginary frequencies for the transition states. The activation energies
À
for the C C bond-formation steps were computed to be 11.6 and
11.9 kcalmolÀ1 for the S and R configurations, respectively.
explained by the interference from the noncatalyzed reaction
and nonstereoselective activation pathways.
The high Z/E ratios of the reaction product suggest that
the proton transfer occurs directly from the nitrogen atom to
the carbon atom, because protonation of the oxygen atom
1
and the Z/E ratios were determined by H NMR spectroscopy. The
ee values were determined by HPLC on a chiral stationary phase
using a Chiralpak AD-H column. Spectroscopic data for the hydro-
genated products are provided in the Supporting Information. The
absolute configuration and the structure of the Z isomer were
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Communications
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CCDC 780649 (5a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
Received: June 12, 2010
Published online: September 20, 2010
Keywords: acetylenic esters · asymmetric conjugate addition ·
.
bifunctional catalysts · density functional calculations ·
ruthenium
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